Insulin resistance, a primary component of the metabolic syndrome, is an escalating phenomenon in the United States, and confers an increased risk of depression and mood disorder, particularly in women. The relationship between metabolic and mood disorders may be mediated by endogenous opioid activity in limbic brain regions. We propose to examine affective state and -opioid system function in insulin resistant women, and change in response to insulin sensitizing treatment, through the following specific aims and hypotheses: Establish relationship between insulin resistance, affective state, and -opioid receptor function. 1. Insulin resistant women will have greater -opioid receptor availability at baseline, and a larger response to stress challenge than non-insulin resistant women 2. Insulin resistant women will have greater negative affective state at baseline, and a greater emotional response to stress challenge than non-insulin resistant women. 3. Mediational analyses will reveal that the relationship between insulin resistance and negative affect is mediated by -opioid receptor function in the amygdala and nucleus accumbens affect-regulating regions. Examine effects of insulin regulation on -opioid receptor function and affective state. 1. Improved insulin sensitivity will be accompanied by decreased -opioid receptor availability at baseline and a reduced response to stress challenge. Degree of change in baseline receptor availability and response to stress challenge after treatment will correlate with degree of insulin regulation. 2. Improved insulin sensitivity will be associated wit improved affective state at baseline, and with a reduced emotional response to stress challenge. Degree of change in affective state and emotional response to stress challenge after treatment will correlate with degree of insulin regulation. 3. Mediational analyses will reveal tha the change in affective state after insulin regulation is mediated by change in -opioid receptor function in the amygdala and nucleus accumbens. The expected results would suggest a role for the endogenous -opioid system in mediating the relationship between metabolic function and emotional processes. In combination with a tailored career development plan and expert mentoring in the fields of human neurobiology, psychiatry, and metabolic endocrinology, this mentored research project will build the skills and experience necessary to lead sophisticated investigation of the effects of endocrine disruption on neurobiology and behavior in women. The relationship between metabolic and mood disorders exemplifies the increasing importance of investigators with multidisciplinary expertise, and the ability to conduct research that traverses traditional disciplinary boundaries.